Circulating bone marrow (BM)-derived cells have been shown to play an important role in normal physiologic maintenance and repair of the body's vasculature with approximately 1-12% of endothelial cells at any one time being BM-derived (Schatteman, G. C. Adult bone marrow-derived hemangioblasts, endothelial cell progenitors, and EPCs, Curr Top Dev Biol 64, 141-80 (2004)). The ability to repair vascular damage could have a profound impact on diabetes induced complications. Diabetes affects 20 million Americans or about 7 percent of the population. Diabetic complications include heart disease, stroke, kidney failure, blindness, as well as nerve and peripheral vascular disease that can lead to lower limb amputations. Furthermore, preventing diabetic complications could save $2.5 billion annually. Recent evidence suggests that hematopoietic stem cells (HSC) differentiate into vascular structures as well as into all hematopoietic cell lineages and this has spawned the era of cellular therapies for vascular insufficency. These therapies are now attempting to replace traditional approaches such as stents, angioplasty or vessel grafts to alleviate tissue ischemia (Losordo, D. W. & Dimmeler, S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies, Circulation 109, 2692-7 (2004)). BM derived cells can differentiate into endothelial cells and these cells are thought to be important in processes such as vasculogenesis and vascular repair. The entire diabetic endothelium suffers damage as a result of oxidative stress and hyperglycemic. Injured macrovasculature endothelium, if not repaired, leads to a propensity for arteriosclerosis. With regard to the microvasculature, this same endothelial damage results in capillary damage in the heart, nerves, skin and retina (Kugler, C. F. & Rudofsky, G. The challenges of treating peripheral arterial disease, Vasc Med 8, 109-14 (2003)).
In capillaries, a defect in the endothelial progenitor cells (EPCs) could prevent reparation of endothelial injury early on leading to tissue ischemia. In the macrovasculature this same inability to repair the endothelium results in an increase in cytokines and up regulation of adhesion molecules with an influx of lipoprotein, monocytes, and T cells; initiating the atherosclerotic lesion (Ross, R., Glomset, J. & Harker, L. Response to injury and atherogenesis, Am J Pathol 86, 675-84 (1977)). Thus the cause of diabetic microvascular and macrovascular dysfunction may be the same; lack of EPC repair of the endothelium.
TGF-β1 is a pleiotropic regulator of all stages of hematopoiesis (Ruscetti, F. W. & Bartelmez, S. H. Transforming growth factor beta, pleiotropic regulator of hematopoietic stem cells: potential physiological and clinical relevance, Int J Hematol 74, 18-25 (2001)). Furthermore, HSC themselves express and secrete active forms of TGF-β (Ruscetti, F. W., Akel, S. & Bartelmez, S. H. Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context. Oncogene 24, 5751-63 (2005)). The three mammalian isoforms (TGF-β1, 2 and 3) have distinct but overlapping effects on hematopoiesis, but TGF-β1 is the predominate expressed gene in HSC. Depending on the differentiation stage of the target cell, the local environment and the concentration of TGF-β, in vivo or in vitro, TGF-β can be pro- or anti-proliferative, pro- or anti-apoptotic, induce or inhibit differentiation, and can inhibit or increase terminally differentiated cell function. Described herein for the first time is the inventors' discovery that transient neutralization of endogenous TGF-β in HSC dramatically increases the vascular reparative potential of circulating HSC.